This proposal focuses on magnetic resonance imaging (MRI) in multiple sclerosis (MS), a chronic disease of the central nervous system that is the most common cause of non-traumatic neurologic disability in young adults and that causes dramatic abnormalities on MRI scans. To study the progression of MS, I will use new MRI techniques, particularly diffusion tensor imaging, to study the links between clinical dysfunction - especially in the visual system - and imaging abnormalities. My hypothesis is that quantitative and functionally relevant measures will substantially improve our ability to monitor MS over time and will therefore be directly applicable to routine patient care and as imaging-based biomarkers for clinical trials of new MS therapies. Proving this hypothesis will require careful acquisition of serial MRI and clinical data from a large cohort of MS patients, together with development of new imaging sequences and innovative analysis of their results. Johns Hopkins University, where I will carry out the mentored portion of the award, offers a particularly rich environment for this research. In addition, my background ideally positions me to carry out this proposal: I am near the end of a seven-year combined residency-fellowship in neurology, diagnostic radiology, and neuroradiology;I completed a Ph.D. in experimental and quantitative systems neurophysiology (including animal experimentation);and I received my undergraduate education in mathematics and physics. With this combination of clinical, laboratory, and quantitative skills, I will develop new imaging methods and refine them into powerful tools to provide crucial information for clinicians working at the patient's bedside. Public Health Relevance: There is both an urgent need and a promising opportunity to develop automated, quantitative methods that are functionally relevant, that are straightforward to use in routine clinical practice, and that can sensitively assess disease progression in multiple sclerosis as well as response to therapy. The proposed research is directed toward this goal, investigating the links between imaging abnormalities and clinical disability, especially in the visual system, and identifying markers for use in clinical care and future drug trials.